Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma, a sight- threatening optic neuropathy that is one of the leading causes of irreversible blindness worldwide. Although current therapies target reduction in IOP, a clinically effective treatment that eradicates progression of visual loss to blindness remains elusive, prompting intense search for potential therapeutic targets. Evidence of the presence of a functional trans-sulfuration pathway in mammalian tissues has stimulated a surge of interest in the biological significance and role of hydrogen sulfide (H2S), a colorless gas with pungent odor of rotten eggs in ocular tissues. To the best of our knowledge, there are few studies that have examined the physiological and/ pharmacological role of H2S (using H2S-releasing compounds) in ocular tissues especially those involved in the regulation of IOP. In this proposed study, we hypothesize that H2S-releasing compounds can regulate IOP and aqueous humor dynamics by an effect that is mediated via conventional and/ uveoscleral pathways. Three specific aims are designed to test the above hypothesis. Specific Aim 1: To determine the effect of H2S- releasing compounds on IOP and aqueous humor dynamics in normotensive rabbits. Specific Aim 2: To investigate the effect and role of H2S-releasing compounds on aqueous humor outflow facility via the conventional and uveoscleral pathway. Specific Aim 3: To determine the mechanism of action of H2S-releasing compounds in regulating aqueous humor outflow. We anticipate that results from the proposed study will demonstrate a physiological/pharmacological role of H2S in the anterior segment of the eye, and also justify the potential use of H2S-based compounds in the development of better and new therapeutic agents for lowering IOP. Furthermore, we expect that findings from this project will be applicable to other ocular diseases, thus opening up new opportunities for the use of H2S-releasing compounds in the preservation of vision. PUBLIC HEALTH RELEVANCE: Due to the fact the current glaucoma therapies do not eradicate loss of vision and replete with side effects, the need to identify additional groups of compounds with specific and potent action on this disease need not be overemphasized. This proposal aims to study the physiological/pharmacological role and mechanism of action of H2S-releasing compounds on ocular tissues of the eye, especially those involved in the regulation of IOP. These studies should provide a better understanding of the role of H2S in diseases of the eye such as glaucoma and aid in identifying better and new classes of IOP-lowering agents with minimal or no adverse effects.